By Hendra Lukman 
The advent of the COVID-19 pandemic thrust messenger RNA (mRNA) vaccines into an unprecedented global spotlight, ushering in a new era of rapid vaccine development and deployment. Following rigorous clinical trials, the first mRNA vaccine against COVID-19 was administered on December 8, 2020, marking a pivotal moment in public health history. Subsequent modeling efforts by researchers estimated that these groundbreaking vaccines averted at least 14.4 million deaths worldwide within their inaugural year, a testament to their profound impact on combating the devastating virus.
This remarkable success catalyzed a surge of scientific interest in exploring mRNA technology for a wider array of infectious diseases. Promisingly, ongoing clinical trials are currently investigating mRNA vaccines for influenza virus, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and even tuberculosis bacteria. However, the very studies that highlighted the triumphs of COVID-19 mRNA vaccines also illuminated critical limitations, underscoring the imperative for continued innovation and the exploration of novel vaccine strategies to address persistent challenges in vaccine performance, production, and accessibility.
Navigating the Hurdles of mRNA Vaccine Performance and Production
Despite their monumental success, COVID-19 mRNA vaccines present several inherent challenges. The immune protection they elicit can exhibit significant inter-individual variability, meaning the strength and duration of immunity can differ substantially from one person to another. Furthermore, this protection is not immutable; it wanes over time. This inherent limitation is exacerbated by the relentless evolution of the SARS-CoV-2 virus, which continuously generates new variants capable of partially evading established immune defenses. Consequently, the need for frequent vaccine updates becomes a recurring necessity, posing logistical and public health complexities.
Beyond performance, practical and logistical hurdles persist. The manufacturing of mRNA vaccines is a complex and resource-intensive undertaking, characterized by high costs and intricate processes. Precisely controlling the quantity of mRNA molecules encapsulated within lipid nanoparticles, a crucial step for vaccine efficacy and stability, remains a significant technical challenge. Additionally, these vaccines typically require stringent cold-chain storage, demanding specialized infrastructure and careful handling throughout the supply chain. The potential for unintended off-target effects, while generally rare and manageable, also remains a consideration in the broader vaccine development landscape. Overcoming these multifaceted limitations is paramount to enhancing global preparedness and refining our response strategies for future infectious disease threats.
The DoriVac Platform: A Novel DNA Origami Approach
In response to these persistent challenges, a multidisciplinary team of researchers from the Wyss Institute at Harvard University, the Dana-Farber Cancer Institute (DFCI), and affiliated institutions has pioneered a distinct and innovative approach. Their work centers on a DNA origami nanotechnology platform named DoriVac, which uniquely functions as both a vaccine delivery system and an adjuvant, a substance that amplifies the immune response.
The researchers strategically designed DoriVac vaccines to target specific peptide regions, known as HR2, found within the spike proteins of a range of viruses, including SARS-CoV-2, HIV, and Ebola. In preclinical studies conducted in mice, a DoriVac vaccine engineered to target the SARS-CoV-2 HR2 peptide elicited robust and multi-faceted immune responses. These included potent antibody-driven (humoral) immunity, crucial for neutralizing pathogens, and T cell-driven (cellular) immunity, essential for clearing infected cells and establishing long-term memory.
To bridge the gap between animal models and human relevance, the team further validated their findings using a sophisticated preclinical human model. This involved the Wyss Institute’s cutting-edge microfluidic human Organ Chip technology, designed to simulate a human lymph node in vitro. Within this intricate system, the SARS-CoV-2 HR2 DoriVac vaccine demonstrated its capacity to generate strong antigen-specific immune responses in human cells, mirroring the promising results observed in mice.
A direct head-to-head comparison with conventional SARS-CoV-2 mRNA vaccines, delivered via lipid nanoparticles, revealed that a DoriVac vaccine carrying the same spike protein variant induced a similarly potent immune activation in these human models. However, the DNA origami vaccine exhibited significant advantages in terms of stability and ease of storage and manufacturing, key factors for broader accessibility and deployment. These groundbreaking findings were recently published in the esteemed journal Nature Biomedical Engineering, marking a significant milestone in vaccine technology.
"With the DoriVac platform, we have developed an extremely flexible chassis with a number of critical advantages, including unprecedented control over vaccine composition, and the ability to program immune recognition in targeted immune cells on a molecular level to achieve better responses," stated co-corresponding author William Shih, Ph.D., a Core Faculty member at the Wyss Institute and a pioneer of this novel vaccine concept. Dr. Shih, who also holds professorships at Harvard Medical School and DFCI, elaborated, "Our study demonstrates DoriVac’s versatility and potential by taking a close look at the immune changes that are required to fight infectious viruses."
The Architecture of DNA Origami Vaccines: Precision Engineering for Immunity
The conceptualization and development of DoriVac as a DNA nanotechnology-based vaccine platform with broad application potential were formally introduced in 2024 by Dr. Shih’s teams at the Wyss Institute and DFCI. Yang (Claire) Zeng, M.D., Ph.D., who spearheaded this extensive research effort alongside collaborators, demonstrated DoriVac’s remarkable ability to precisely present immune-stimulating adjuvant molecules to cells at the nanoscale, a level of control previously unattainable.
Earlier investigations utilizing DoriVac in tumor-bearing mice had already showcased its superior capacity to generate stronger immune responses compared to vaccine formulations lacking the DNA origami structure. The construction of DoriVac vaccines involves intricate self-assembly of minuscule square DNA nanostructures. One face of these nanostructures is meticulously engineered to display adjuvant molecules arranged at precisely controlled nanometer distances, optimizing their interaction with immune cells. The opposing face is designed to present selected antigens, such as peptides or proteins derived from tumors or pathogens, thereby guiding the immune system’s recognition and response.
"While we were developing the platform for cancer applications, the COVID-19 pandemic was still moving with full force. So, the question quickly arose whether DoriVac’s superior adjuvant activity could also be leveraged in infectious disease settings," explained Dr. Zeng, who served as the first and co-corresponding author on the new study and is now co-founder and CEO/CTO of DoriNano, an entity dedicated to translating this technology into clinical applications.
Driven by this pivotal question, Dr. Zeng and co-first author Olivia Young, Ph.D., a former graduate student in Dr. Shih’s group, forged a collaborative partnership with Donald Ingber’s distinguished team at the Wyss Institute. Dr. Ingber’s group is renowned for its pioneering work in antiviral innovation, employing artificial intelligence-driven and multiomics approaches alongside advanced microfluidic human Organ Chip systems. In conjunction with co-first author Longlong Si, Ph.D., a former postdoctoral researcher in Dr. Ingber’s lab, the researchers successfully developed DoriVac vaccines targeting SARS-CoV-2, HIV, and Ebola. These innovative vaccines are engineered to present HR2 peptides, which function as conserved antigens within the highly variable viral spike proteins, offering a more stable target for immune recognition.
"Our analysis of the immune responses provoked by these first DoriVac vaccines in mice led to several encouraging observations, including significantly greater and broader activation of humoral and cellular immunity across a range of relevant immune cell types than what the origami-free antigens and adjuvants could produce," Dr. Zeng reported. She further elaborated on the specific immune enhancements: "We found that the numbers of antibody-producing B cells, activated antigen-presenting dendritic cells (DCs), and antigen-specific memory and cytotoxic T cell types that are vital for long-term protection were all increased, especially in the case of the SARS-CoV-2 HR2."
Bridging the Mouse-to-Human Gap: Advanced Human Models for Predictive Power
A persistent and significant challenge in vaccine development lies in the often-limited correlation between immune responses observed in mice and those that manifest in humans. This translational gap has historically led to the failure of numerous promising preclinical candidates during human clinical trials. To enhance the predictive accuracy of their findings and better anticipate human outcomes, the research team ingeniously employed a human lymph node-on-a-chip (human LN Chip) system. This advanced microfluidic device meticulously mimics critical aspects of the human immune system, offering a more human-relevant testing ground.
This sophisticated system, further advanced by co-first author Min Wen Ku and co-corresponding author Girija Goyal, Ph.D., Director of Bioinspired Therapeutics at the Wyss Institute, provided compelling evidence of DoriVac’s efficacy in human cells. The SARS-CoV-2-HR2 DoriVac vaccine demonstrably activated human dendritic cells (DCs) and significantly amplified their production of inflammatory cytokines, crucial signaling molecules for immune activation, when compared to non-origami control components. Moreover, it substantially increased the number of CD4+ and CD8+ T cells, which possess multiple protective functions, thereby strongly supporting the platform’s considerable potential for direct human application.
"The predictive capabilities of human LN Chips gave us an ideal testing ground for DoriVac vaccines and the induced, antigen-specific immune cell profiles and activities very likely reflect those that would occur in human recipients of the vaccines," commented co-corresponding author Donald Ingber, M.D., Ph.D. Dr. Ingber, who also holds distinguished professorships at Harvard Medical School, Boston Children’s Hospital, and the Harvard John A. Paulson School of Engineering and Applied Sciences, emphasized the synergistic impact of these technologies: "This convergence of technologies enabled us to dramatically raise the chances of success for a new class of vaccines and create a new testbed for future vaccine developments."
Head-to-Head Comparison: DoriVac vs. mRNA Vaccines
In a critical evaluation of DoriVac’s competitive potential, the researchers conducted a direct comparison between a DoriVac vaccine designed to present the full SARS-CoV-2 spike protein and commercially available mRNA lipid nanoparticle (LNP) vaccines from Moderna and Pfizer/BioNTech, which encode the identical spike protein. This rigorous head-to-head analysis, led by Dr. Zeng and co-author Qiancheng Xiong, aimed to assess the comparative immunogenicity and efficacy of the two platforms.
Utilizing a standard booster vaccination approach in mice, both the DoriVac vaccine and the established mRNA-LNP vaccines elicited comparable levels of antiviral T cell responses and antibody-producing B cell activity. This finding underscored the robust immunogenic potential of the DoriVac platform.
"This underscored DoriVac’s potential as a DNA nanotechnology-enabled, self-adjuvanted vaccine platform. But DoriVac vaccines have a number of other advantages: they don’t have the same cold-chain requirements as mRNA-LNP vaccines do and thus could be distributed much more effectively, especially in under-resourced regions; and they could overcome some of the enormous manufacturing complexities of LNP-formulated vaccines, to name two major ones," Dr. Shih articulated, highlighting the pragmatic benefits of the DoriVac approach. Furthermore, recent preliminary studies conducted at DoriNano have indicated that DoriVac exhibits a promising safety profile, a critical factor for widespread clinical adoption.
The comprehensive study involved a significant collaborative effort, with contributions from numerous researchers including Sylvie Bernier, Hawa Dembele, Giorgia Isinelli, Tal Gilboa, Zoe Swank, Su Hyun Seok, Anjali Rajwar, Amanda Jiang, Yunhao Zhai, LaTonya Williams, Caleb Hellman, Chris Wintersinger, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Sarai Bardales, Georgia Tomaras, Ju Hee Ryu, and Ick Chan Kwon. Funding for this extensive research was generously provided by the Director’s Fund and Validation Project program of the Wyss Institute; the Claudia Adams Barr Program at DFCI; the National Institutes of Health (U54 grant CA244726-01); the US-Japan CRDF Global Fund (grant R-202105-67765); the National Research Foundation of Korea (grants MSIT, RS-2024-00463774, RS-2023-00275456); the Intramural Research Program of the Korea Institute of Science and Technology (KIST); and the Bill and Melinda Gates Foundation (INV-002274). The collective efforts of these institutions and individuals underscore the significant investment and collaborative spirit driving the advancement of novel vaccine technologies like DoriVac.
